Process for preparing alkoxypyrazine derivatives

ABSTRACT

A process for preparing alkoxypyrazine derivatives of the general formula:  
                 
 
     These alkoxypyrazine derivatives are obtained by reacting a glyoxal derivative of the general formula:  
                 
 
     and an amimoimidate of the general formula:  
                 
 
     The alkoxypyrazine derivatives are important intermediates for preparing pharmaceutically active compounds.

BACKGROUND OF THE INVENTION

[0001] 1. Field of the Invention

[0002] The invention relates to a novel process for preparingalkoxypyrazine derivatives of the general formula:

[0003] in which R¹denotes hydrogen, alkyl or aryl, R² denotes hydrogen,alkyl, —CONH₂, —COOR⁴, in which R⁴ denotes alkyl, or —C(NH)OR⁴, in whichR⁴ is as defined above, and R³ denotes alkyl or aryl. Moreover, theinvention relates to a novel process for preparing alkoxypyrazineaminederivatives of the general formula:

[0004] in which R¹ and R³ are as defined above.

[0005] 2. Background Art

[0006] Both the alkoxypyrazine derivatives of the general formula Ia andthe alkoxypyrazineamine derivatives of the general formula V areimportant intermediates for preparing pharmaceutically active compounds[Katritzky, Comprehensive Het. Chem.,Vol. 3, (1984), 179-197].

[0007] A number of processes for preparing pyrazine derivatives areknown from the above-mentioned literature reference.

[0008] British Published Patent Application No. 922,725, for example,describes a process for preparing 3-methoxy-5-methylpyrazine-2-amine byreaction of 3-chloro-5-methylpyrazine-2-amine with sodium methoxide.

BROAD DESCRIPTION OF THE INVENTION

[0009] It is an object of the present invention to provide a novelalternative access to alkoxypyrazine and alkoxypyrazineaminederivatives. This object is successfully achieved by the novel processaccording to the invention.

[0010] The key step of the synthesis according to the inventionaccording to the first process of the invention is the reaction of aglyoxal derivative of the general formula:

[0011] in which R¹ is as defined above with an aminoimidate of thegeneral formula:

[0012] in which R² and R³ are as defined above to give thealkoxypyrazine derivative of the general formula:

[0013] in which R¹ denotes hydrogen, alkyl or aryl, R² denotes hydrogen,alkyl, —CONH₂, —COOR⁴, in which R⁴ denotes alkyl, or —C(NH)OR⁴, in whichR⁴ is as defined above, and R³ denotes alkyl or aryl.

[0014] The radicals R¹ to R⁵ are as defined below:

[0015] Alkyl denotes a C₁-C₆-alkyl group, specifically methyl, ethyl,n-propyl, isopropyl, n-butyl, isobutyl, t-butyl, pentyl and its isomersand hexyl and its isomers.

[0016] Alkyl preferably denotes a C₁-C₄-alkyl group. The alkyl group canoptionally be substituted by one of the alkyl groups mentioned, by aryl,by a halogen, by an alkoxy group, by an amino, by an alkylamino or by adialkylamino group.

[0017] For the purpose of the invention, aryl is to be understood as anoptionally substituted phenyl or naphthyl group. Suitable substituentsare the above-mentioned alkyl groups, halogen, alkoxy, amino, alkylaminoor dialkylamino.

[0018] The preferred aryl group is phenyl. The preferredaryl-substituted alkyl group is benzyl. For the purpose of theinvention, halogen denotes fluorine, chlorine, bromine or iodine,preferably chlorine.

[0019] Depending on the substitution pattern of the reactants, the groupR¹ can be positioned regioselectively in position 5 or position 6 of thealkoxypyrazine derivative.

[0020] Generally and also preferably, an alkoxypyrazine derivative ofthe general formula:

[0021] results in which R¹ is in position 5.

[0022] The glyoxal derivatives of the general formula II are generallyavailable commercially. This is true in particular for the preferablyused compounds glyoxal (R¹=H), methylglyoxal (R¹=CH₃) and phenylglyoxal(R¹= phenyl). However, it is also possible to employ other glyoxalcompounds of the general formula II where R¹= t-butyl or haloalkyl, suchas, for example, di- or triflhalomethyl, in particular di- ortrifluoromethyl or di-trichloromethyl.

[0023] The aminoimidate of the general formula III used as reactionpartner of the glyoxal derivative of the general formula II is acompound whose presence can be reaffirmed unambiguously, but which canusually not be isolated in stable form. According to one subembodimentof the invention, the aminoimidate of the general formula III istherefor advantageously prepared by reacting an aminonitrile of thegeneral formula:

[0024] in which R⁵ has the meaning of R² or of cyano, with an alkalimetal alkoxide or alkaline earth metal alkoxide and then reactedfurther, directly and without isolation, with the glyoxal derivative ofthe general formula II to give the alkoxypyrazine derivative of thegeneral formula Ia.

[0025] The reaction is advantageously carried out by initially chargingthe amino nitrile of the general formula IV in a suitable solvent,preferably in an aliphatic alcohol, followed by reaction with the alkalimetal alkoxide or alkaline earth metal alkoxide in question at atemperature of advantageously −30° C. to 150° C.

[0026] Preference is given to using alkali metal alkoxides, such assodium methoxide or potassium methoxide or sodium ethoxide or potassiumethoxide.

[0027] Depending on the group R² in the resulting aminoimidate of thegeneral formula III, it may be advantageous to neutralize the reactionmixture with a suitable acid beforehand.

[0028] Suitable acids are simple carboxylic acids, such as acetic acid,or mineral acids, such as, sulfuric acid or hydrochloric acid.

[0029] The aminoimidate of the general formula III can usually not beisolated in stable form, but its presence can be reaffirmedunambiguously by spectroscopic methods such as ¹³C NMR. Consequently,further reaction with the glyoxal derivative usually follows. This isadvantageously carried out at a temperature of −30° C. to 150° C.,preferably of −10° C. to 10° C.

[0030] The glyoxal derivative of the general formula II is usuallyemployed in a slight excess, based on the aminonitrile of the generalformula IV.

[0031] The reaction has usually ended after 0.1 hour to 40 hours, andthe alkoxypyrazine of the general formula I can then be isolated in acustomary manner, for example by extraction from the reaction mixture.

[0032] Alkoxypyrazine derivatives of the general formula Ia where R¹andR³ denote alkyl or aryl and R² denotes —CONH₂, COOR⁴, where R⁴ denotesaikyl, or —C(NH)OR⁴, where R⁴ is as defined above, are novel and notknown from the literature and are therefore also part of thesubject-matter of the present invention. Specifically, such novelalkoxypyrazine derivatives are:

[0033] 3-methoxy-5-methylpyrazine-2-carboxamide;

[0034] 3-ethoxy-5-methylpyrazine-2-carboxamide;

[0035] methyl 3-methoxy-5-methylpyrazine-2-carboxylate;

[0036] methyl 3-ethoxy-5-methylpyrazine-2-carboxylate;

[0037] 3-methoxy-5-phenylpyrazine-2-carboxamide:

[0038] 3-ethoxy-5-phenylpyrazine-2-carboxamide;

[0039] methyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate;

[0040] methyl 3-ethoxy-5-methylpyrazine-2-imidocaroxylate;

[0041] ethyl 3-methoxy-5-methylpyrazine-2-carboxylate; and

[0042] ethyl 3-ethoxy-5-methylpyrazine-2-carboxylate.

[0043] The reaction according to the invention is preferably suitablefor preparing 3-methoxy-5-methylpyrazine-2-carboxamide (general formulaIb where R¹ denotes methyl, R² denotes —CONH₂, and R³ denotes methyl).To this end, either 2-amino-2-cyanoacetamide (general formula IV whereR⁵ denotes —CONH₂) or 2-aminomalononitrile (general formula IV where R⁵denotes —CN), or a salt thereof, can be used as the starting material.

[0044] Starting from 2-amino-2-cyanoacetamide, the target compound isobtained by the above-described reaction with the alkali metal alkoxideor alkaline earth metal alkoxide and subsequent neutralization via theaminoimidate intermediate (general formula III where R² denotes —CONH₂and R³ denotes methyl) and after reaction with methylglyoxal (generalformula II where R¹ denotes methyl).

[0045] Starting from 2-aminomalononitrile, or a salt thereof, the targetcompound is obtained by the above-described reaction with the alkalimetal alkoxide or alkaline earth metal alkoxide and subsequentneutralization via the aminoimidate intermediate (general formula IIIwhere R² denotes —C(NH)OCH₃ and R³ denotes methyl), after its reactionwith methylglyoxal (general formula II where R¹ denotes methyl) viamethyl 3-methoxy-5-methylpyrazine-2-imidocarboxylate, after itsacidification to give methyl 3-methoxy-5-methylpyrazine-2-carboxylateand finally after its amidation.

[0046] In the last variant, methyl3-methoxy-5-methylpyrazine-2-imidocarboxylate is not isolated butdirectly converted into the carboxylic ester mentioned by acidificationof the reaction mixture. The acidification and the amidation is carriedout in a known manner using a mineral acid and ammonia, respectively.

[0047] The alkoxypyrazine derivatives of the general formula Iapreparable according to the invention where R² denotes —CONH₂ and R¹ andR³ are defined as above, can, according to a further aspect of theinvention, be converted, according to the principles of the Hofmanndegradation, into alkoxypyrazineamine derivatives of the generalformula:

[0048] where R¹ and R³are as defined above, using an alkali metalhypohalite.

[0049] Preference is given to preparing, starting from thealkoxypyrazine derivatives of the general formula Ib, thealkoxypyrazineamine derivatives of the general formula:

[0050] in which R¹and R³ are as defined above.

[0051] The Hofmann degradation is known from the literature. Thereaction is usually carried out using an alkali metal hypobromitesolution, which is customarily prepared from the corresponding alkalimetal hydroxide and bromine, at a reaction temperature between −20° C.and 100° C.

[0052] The alkoxypyrazineamine derivative can be isolated from thereaction mixture in a customary manner known to the person skilled inthe art, for example, by extraction.

DETAILED DESCRIPTION OF THE INVENTION EXAMPLE 1 (a) Synthesis of methyl(2-amino-2-carbonyl)acetoimidate

[0053] Under argon, 1.09 g (10.3 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 11 g of methanol. 0.29 g (1.6 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 20° C.for 2 hours. The structure of the title product was confirmed by NMR,with the data being: ¹H-NMR (DMSO-d₆, 400 MHz)δ: 3.85 (s, 3H); 4.18 (s,1H); 8.2-8.6 (sb, 1H). ¹³C-NMR (DMSO-d₆, 400 MHz)δ: 52.27 (q); 55.83(d); 171.66 (s); 172.78 (s).

(b) Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

[0054] Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 67 g of methanol. 1.67 g (9.3 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred for at20° C. 2 hours. After nuetralization with 0.558 g (9.3 mmol) of aceticacid, 11.55 g (64.1 mmol) of methylglyoxal solution (40%) was added. Themixture was stirred at 20° C. for 2 hours and then at 50° C. for 2hours. The solvent was distilled off and the3-methoxy-5-methylpyrazine-2-carboxamide was purified by columnchromatography (eluent:ethyl acetate/methanol 4:1). This gave 5 g of3-methoxy-5-methylpyrazine-2-carboxamide. The yield was 50 percent.Other data concerning the title product was: ¹H-NMR (DMSO-d₆, 400 MHz)δ:8.10(s, 1H); 7.84 and 7.56 (2s, broad 2H); 3.93 (s, 3H); 2.46 (s, 3H).¹³C-NMR (DMSO-d₆, 400 MHz)δ: 165.5 (s); 156.6 (s); 152.4 (s); 134.5 (s);134.3 (d); 53.4 (q); 20.7 (q).

(c) Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

[0055] Under argon, 6 g (60.5 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 67 g of methanol. 1.67 g (9.3 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 20° C.for 2 hours. At 0° C., 11.55 g (64.1 mmol) of methylglyoxal solution(40%) was added and the mixture was stirred at 0° C. for 2 hours. Thesolution was then cooled to −20 ° C. The product precipitated out. Afterfiltration and drying, 3.56 g of the title product was obtained. Theyield was 39 percent. The melting point of the title product was 170° C.to 172° C. Other data concerning the title product was: ¹H-NMR (DMSO-d₆,400 MHz)δ: 810 (s, 1H); 7.84 and 7.56 (2s broad, 2H); 3.93 (s, 3H); 2.46(s, 3H). ¹³C-NMR (DSMO-d₆, 400 MHz)δ: 165.5 (s); 156.6 (s); 152.4 (s);134.5 (s); 134.3 (d); 53.4 (q); 20.7 (q).

EXAMPLE 2 (a) Synthesis of 3-methoxy-5-methylpyrazine-2-amine

[0056] 3.71 g (56.2 mmol) of potassium hydroxide (85%) and 31 g of waterwere initially charged in a flask. At 1° C., 2.16 g (13.5 mmol) ofbromine was added dropwise over a period of 10 minutes. This potassiumhypobromite solution was added dropwise at 4° C. to an aqueous solutionof 2.27 g (13.1 mmol) of 3-methoxy-5-methylpyrazine-2-carboxamide in 12g of water. The mixture was stirred at 1° C. for one hour and then at98° C. for 3 hours. The resultant 3-methoxy-5-methylpyrazine-2-amine wasextracted at 20° C. using methylene chloride (2 times 25 ml). Removal ofthe solvent gave 0.92 g of 3-methoxy-5-methylpyrazine-2-amine. The yieldwas 50.4 percent. The melting point of the title product was 75° C. to76.5° C. The other data concerning the title product was: ¹H-NMR(DMSO-d₆, 400 MHz)δ; 2.20 (s, 3H); 3.87 (s, 3H); 5.90 (s, 2H); 7.33 (s,1H).

(b) Synthesis of 3-methoxy-5-methylpyrazine-2-amine

[0057] 1.54 g (23.3 mmol) of potassium hydroxide (85%) and 15 g of waterwere initially charged in a flask. At 1° C., 1.08 g (5.53 mmol) ofbromine was added dropwise over a period of 10 minutes. This potassiumhypobromite solution was added dropwise at 4° C. to an aqueous solutionof 1.04 g (5.76 mmol) of 3-methoxy-5-methylpyrazine-2-carboxamide in 6.5g of water. The mixture was stirred at 1° C. for 1 hour and then at 83 °C. for 3 hours. The 3-methoxy-5-methylpyrazine-2-amine was extracted at20° C. using methylene chloride (2 times 15 ml). Removal of the solventgave 0.65 g of the title product. The yield was 80 percent. The meltingpoint of the title product was 75° C. to 76.5° C. Other data concerningthe title product was: ¹H-NMR (DMSO-d₆, 400 MHz)δ; 2.20 (s, 3H); 3.87(s, 3H); 5.90 (s, 2H); 7.33 (s, 1H).

EXAMPLE 3 Synthesis of 3-methoxypyrazine-2-carboxamide

[0058] Under argon, 1 g (10.1 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 10 g of methanol. 0.25 g (1.4 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 20° C.for 2 hours. After neutralization with 0.084 g (1.4 mmol) of aceticacid, 2.27 g (20 mmol) of glyoxal solution (40%) was added. The mixturewas stirred at 20° C. for 2 hours and then at 50° C. for 2 hours. Thesolvent was distilled off. This gave 0.75 g of3-methyoxypyrazine-2-carboxamide. The yield was 50 percent. Other dataconcerning the title product was: ¹H-NMR (DMSO-d₆, 400 MHz)δ: 3.18 (s,3H); 3.95 (s, 3H); 7.63 (s, 1H); 7.93 (s, 1H); 8.22 (d, 1H, J = 1Hz);8.37 (d, 1H, J = 1Hz).

EXAMPLE 4 Synthesis of Methyl 3-methoxy-5-methylpyrazine-2-carboxylate

[0059] Under argon, 5 g (19.3 mmol) of2-aminomalononitrile-4-toluenesulfonate was initially charged in 50 g ofmethanol. 4.09 g (22.7 mmol) of sodium methoxide solution (30%) wasadded and the mixture was stirred at 2° C. for 2 hours. Afterneutralization with 0.204 g (3.4 mmol) of acetic acid, 3.6 g (19.9 mmol)of methylglyoxal solution (40%) was added. The mixture was stirred at40° C. for 2 hours and then, at 20° C., 9.2 g (80 mmol) of hydrochloricacid (32%) was added and the mixture was stirred at 20° C. for 6 hours.The solvent was distilled off and the methyl3-methoxy-5-methylpyrazine-2-carboxylate was extracted with methylenechloride. This gave 1 g of methyl3-methoxy-5-methylpyrazine-2-carboxylate. The yield was 27 percent.Other data concerning the title product was: ¹H-NMR (CDCl₃, 400 MHz)δ:2.54 (s, 3H); 3.98 (s, 3H); 4.07 (s, 1H); 8.12 (s, 1H). ¹³C-NMR (CDCl₃,400 MHz)δ: 21.4 (q); 52.7 (q); 54.2 (q); 129.7 (s); 135.4 (d); 155.4(s); 158.9 (s); 164.3 (s).

EXAMPLE 5 Synthesis of 3-methoxy-5-methylpyrazine-2-carboxamide

[0060] 1 g (5.5 mmol) of methyl 3-methoxy-5-methylpyrazine-carboxylatewas initially charged in 15 ml (198 mmol) of NH₃ (25%) and the mixturewas stirred at 50° C. After concentration, 0.8 g of3-methoxy-5-methylpyrazine-2-carboxamide was obtained. The yield was 86percent. Other data concerning the title product was: ¹H-NMR (DMSO-d₆,400 MHz)δ; 8.10 (s, 3H); 7.84 and 7.56 (2s broad, 2H); 3.93 (s, 3H);2.46 (s, 3H).

EXAMPLE 6 Synthesis of 3-methoxy-5-phenylpyrazine-2-carboxamide

[0061] Under argon, 2 g (20 mmol) of 2-amino-2-cyanoacetamide wasinitially charged in 15 g of methanol. 0.55 g (3 mmol) of sodiummethoxide solution (30%) was added and the mixture was stirred at 20° C.for 2 hours. At 0° C., 3.2 g (21 mmol) of phenylglyoxal was added andthe mixture was then stirred at 0° C. for 2 hours and concentrated. Theproduct was purified by column chromatography (eluent ethylacetate/methanol 4/1). This gave 3 g of3-methoxy-5-phenylpyrazine-2-carboxamide. The yield was 65 percent.Other data concerning the title product was: ¹H-NMR (DMSO-d₆, 400 MHz)δ:4.04 (s, 3H); 7.5-8.0 (m, 7H); 8.83 (s, 1H). ¹³C-NMR (DMSO-d₆, 400MHz)δ: 53.45; 127; 128.7; 130.24; 131.7; 134.99; 135.90; 149.4; 156.66;165.3. 229 (100%)

What is claimed is:
 1. A process for preparing an alkoxypyrazinederivative of the formula:

in which R¹ denotes hydrogen, alkyl or aryl, R² denotes hydrogen, alkyl,—CONH₂, —COOR⁴, in which R⁴ denotes alkyl, or —C(NH)OR⁴, in which R⁴ isas defined above, and R³ denotes alkyl or aryl, comprising reacting aglyoxal derivative of the formula:

in which R¹is as defined above, with an aminoimidate of the formula:

in which R² and R³ are as defined above.
 2. The process according toclaim 1 , wherein the aminoimidate of the formula III is prepared byreacting an aminonitrile of the formula:

in which R⁵ has the meaning of R² or of cyano, with an alkali metalalkoxide or alkaline earth metal alkoxide and is then reacted further,directly and without isolation, with the glyoxal derivative or theformula II to give the alkoxypyrazine derivative of the formula I. 3.The process according to claim 2 for preparing3-methoxy-5-methylpyrazine-2-carboxamide, wherein2-amino-2-cyanoacetimide is converted, using an alkali metal alkoxide oralkaline earth metal alkoxide and subsequently neutralization, into theaminoimidate of the formula III in which R² denotes —CONH₂ and R³denotes methyl, and said aminoimidate is reacted, without isolation,with methylglyoxal.
 4. The process according to claim 2 for preparing3-methoxy-5-methylpyrazine-2-carboxamide, wherein 2-aminomalononitrile,or salt thereof, is converted, using an alkali metal alkoxide oralkaline earth metal alkoxide and subsequent neutralization, into theaminoimidate of the formula III in which R² denotes —C(NH)OCH₃ and R³denotes methyl, said aminoimidate is reacted, without isolation, withmethylglyoxal and, after acidification, initially converted into methyl3-methoxy-5-methylpyrazine-2-carboxylate, and the ester function isfinally amidated.
 5. The process according to claim 4 . wherein thereaction with an alkali metal alkoxide or alkaline earth metal alkoxideand the reaction with the glyoxal derivative is carried out at atemperature of between −30° C. and 150° C.
 6. The process according toclaim 1 for preparing 3-methoxy-5-methylpyrazine-2-carboxamide, wherein2-amino-2-cyanoacetamide is converted, using an alkali metal alkoxide oralkaline earth metal alkoxide and subsequently neutralization, into theaminoimidate of the formula III in which R² denotes —CONH₂ and R³denotes methyl and said aminoimidate is reacted, without isolation, withmethylglyoxal.
 7. The process according to claim 1 for preparing3-methoxy-5-methylpyrazine-2-carboxamide, wherein 2-aminomalononitrile,or a salt thereof, is converted, using an alkali metal alkoxide oralkaline earth metal alkoxide and subsequent neutralization, into theaminoimidate of the formula III in which R² denotes —C(NH)OCH₃ and R³denotes methyl, said aminoimidate is reacted, without isolation, withmethylglyoxal and, after acidification, initially converted into methyl3-methoxy-5-methylpyrazine-2-carboxylate, and the ester function isfinally amidated.
 8. The process according to claim 1 , wherein thereaction with an alkali metal alkoxide or alkaline earth metal alkoxideand the reaction with the glyoxal derivative is carried out at atemperature of between −30° C. and 150° C.
 9. An alkoxypyrazinederivative of the formula:

in which R¹and R³ denote alkyl or aryl and R² denotes CONH₂, COOR⁴, inwhich R⁴ denotes alkyl, or C(NH)OR⁴, in which R⁴ is as defined above.10. The alkoxypyrazine derivative of the formula Ia according to claim 9, which is selected from the group consisting of:3-methoxy-5-methylpyrazine-2-carboxamide;3-ethoxy-5-methylpyrazine-2-carboxamide; methyl3-methoxy-5-methylpyrazine-2-carboxylate; methyl3-ethoxy-5-methylpyrazine-2-carboxylate;3-methoxy-5-phenylpyrazine-2-carboxamide;3-ethoxy-5-phenylpyrazine-2-carboxamide; methyl3-methoxy-5-methylpyrazine-2-imidocarboxylate; methyl3-ethoxy-5-methylpyrazine-2-imidocarboxylate; ethyl 3-methoxy-5-methylpyrazine-2-carboxylate; and ethyl3-ethoxy-5-methylpyrazine-2-carboxylate.
 11. The process for preparingan alkoxypyrazineamine derivative of the formula:

in which R¹ denotes hydrogen, alkyl or aryl, and R³ denotes alkyl oraryl, wherein an alkoxypyrazine derivative, prepared according to claim1 , of the formula:

in which R¹ denotes hydrogen, alkyl or aryl, R² denotes —CONH₂, and R³denotes alkyl or aryl, is reacted with an alkali metal hypohalite. 12.The process for preparing an alkoxypyrazineamine derivative of theformula:

in which R¹ denotes hydrogen, alkyl or aryl, and R³ denotes alkyl oraryl, wherein an alkoxypyrazine derivative, prepared according to claim1 of the formula:

in which R¹ denotes hydrogen, alkyl or aryl, R² denotes —CONH₂, and R³denotes alkyl or aryl, is reacted with an alkali metal hypohalite.